On February 7, the FDA issued a proposal designed to assist companies developing new treatments for patients in the early stages of Alzheimer’s disease, before the onset of noticeable (overt) dementia.

Although we have an enormous amount of information about the underlying molecular pathophysiology of Alzheimer’s disease, translating this knowledge into effective new treatments has been exceedingly difficult. Part of this difficulty arises from the slowly progressive nature of the disorder. We have known for many decades that the accumulation in the brain of a protein known as amyloid is a central part of this process. Abnormal accumulation of amyloid triggers many other biochemical processes that lead to neuronal cell death and dysfunction that cause cognitive deterioration characteristic of the disease. This understanding has led to the development of many drugs that have the potential to prevent or oppose the abnormal accumulation of amyloid. However, these new drugs have typically been tested in patients in whom cognitive impairments are already fairly far advanced. Yet in recent years, advances in imaging technology and neuropathology have indicated that amyloid accumulation may begin years, or even decades before the appearance of measurable cognitive deficits. Such findings imply that interventions targeting amyloid accumulation are unlikely to show significant clinical benefits if they are not used until cognitive deficits have manifested. Instead, medicines that target amyloid accumulation and other fundamental molecular processes should probably be introduced well in advance of the onset of cognitive changes in order to be optimally effective. This understanding has led to a fundamental rethinking of the methods and strategies for drug development in Alzheimer’s disease. Recognizing these new challenges that face the field, the FDA has developed a draft guidance document for the development of drugs to treat early stages of Alzheimer’s disease. The guidance identifies a number of critical drug development issues and has indicated potential solutions that could move the field forward. In an accompanying press release, Russell Katz, M.D., Director of the Division of Neurology Products at the FDA’s Center for Drug Evaluation and Research noted: “The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain. It is in this population that most researchers believe that new drugs have the best chance of providing meaningful benefit to patients.”

Perhaps the most problematic issue is that of identifying appropriate patient populations to study. Conventional clinical trials involving Alzheimer therapeutics typically enroll patients who meet criteria for a mild to moderate level of dementia as measured by various cognitive tests. Currently, there are a number of diagnostic entities that have been defined so as to capture patient populations at an early stage. These include Mild Cognitive Impermanent (MCI) and prodromal Alzheimer’s disease. However, these diagnoses still depend on identification of some level of cognitive dysfunction. To identify patients at even earlier stages may require the use of genetic and other biomarkers. In developing their industry guidance, the FDA has acknowledged the potential importance of conducting trials in enriched populations defined by combinations of clinical findings and biomarkers. Unfortunately, to date, no biomarkers have been identified with sufficient predictive power. However, a great deal of progress is being made in this area.

The development of treatments for early stage Alzheimer’s disease may also require the development of innovative outcome measures. Conventional studies of mild to moderate Alzheimer’s disease typically employ cognitive testing used in combination with either a functional or global outcome measure as a co-primary endpoint. In the FDA guidance, it is acknowledged that in early stage Alzheimer’s subjects, there may be little or no functional impairment. Therefore, it is recognized that in some cases the use of a co-primary outcome measure may be impractical. However, it is noted that as patients progress to later stages in which both functional and cognitive impairment begin to manifest, it may be appropriate to use composite scales that capture elements of function and cognition. The Clinical Dementia Rating Scale–Sum of Boxes score, which is been validated in patients whose level of impairment does not meet the threshold of frank dementia, is given in the guidance as an example of such a scale,. In the draft guidance, the possibility was also raised that a treatment might obtain approval under the accelerated approval mechanism based on effects demonstrated on an isolated cognitive measure. It was noted that in this scenario a sponsor might be required to demonstrate sustained global effects as a post-marketing condition.

The draft guidance contains an extensive discussion of the topic of biomarkers as primary and secondary outcome measures. It is noted that the use of a biomarker as a primary efficacy endpoint is a theoretical possibility under the accelerated approval mechanism, but there is currently no biomarker for which there is sufficient evidence to justify its use as a proxy for clinical preventive Alzheimer’s disease. The draft guidance states “until there is widespread evidence-based argument in the research community that in effect on the particular biomarker is reasonably likely to predict clinical benefit, we will not be in a position to consider approval based on the use of a biomarker as a surrogate outcome measure in Alzheimer’s disease (at any stage of illness).”

While many issues such as the potential role of biomarkers will have to await scientific development within the field, the development of an industry guidance document represents an important step that will focus the energies of the research community and enable much-needed progress in Alzheimer research. The agency is currently seeking public comments on the draft guidance. It is likely that they will begin finalization of the document next month. The FDA proposal is part of U.S. Department of Health and Human Services initiative known as the National Plan to Address Alzheimer’s Disease. This calls for both the government and the private sector to intensify efforts to treat or prevent Alzheimer’s and related dementias and to improve care and services.